Is SETD2 p.Arg472His (c.1415G>A) pathogenic?

SETD2 p.Arg472His (c.1415G>A) is classified Benign/Likely benign in SETD2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.0881); Rare (popmax 0.105%, nfe); Associated with Luscan-Lumish syndrome.

What condition is associated with SETD2 p.Arg472His (c.1415G>A)?

SETD2 p.Arg472His (c.1415G>A) is associated with Luscan-Lumish syndrome (ClinVar).

How common is SETD2 p.Arg472His (c.1415G>A) in the general population?

SETD2 p.Arg472His (c.1415G>A) is rare (popmax 0.105%, nfe) (gnomAD).

What do computational predictors say about SETD2 p.Arg472His (c.1415G>A)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

SETD2 p.Arg472His

c.1415G>A · rs201984344 · VCV707707

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Luscan-Lumish syndrome

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,229 bp · p 0.25 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.105% European (non-Finnish) · 1,210/1,153,564 alleles

Filtering AF 0.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.098%

Overall 0.0841% 1,318/1,566,436 alleles · rare exomes 1,249/1,414,176 · genomes 69/152,260 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.105%	953
African / African-American	0.0625%	1,599
Remaining individualsnot grpmax-eligible	0.0527%	1,898
Finnishnot grpmax-eligible	0.0195%	5,125
Admixed American	0.0172%	5,822
East Asian	0.00949%	10,537
South Asian	0.00461%	21,685
Ashkenazi Jewishnot grpmax-eligible	0.00346%	28,888

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SETD2
Protein: p.Arg472His
Coding: c.1415G>A
MANE Select: NM_014159
dbSNP: rs201984344
Type: single nucleotide variant
Location: chr3:47123221 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.81 · 43 PDB
Residue 472: a UniProt-annotated variant site (in aml; uncertain significance; somatic mutation); the 'disordered' region

Full SETD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Luscan-Lumish syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD2 p.Arg472Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
SETD2 p.Arg1598Ter Pathogenic/Likely pathogenic ★★ same condition
SETD2 p.Arg1740Gln Pathogenic ★★ ⚠ same condition
SETD2 p.Arg1740Trp Pathogenic/Likely pathogenic ★★ same condition
SETD2 p.Ala1121Thr Uncertain significance ★★ ⚠ same condition
SETD2 p.Ala679Val Uncertain significance ★★ ⚠ same condition
SETD2 p.Arg1065Cys Uncertain significance ★★ same condition
SETD2 p.Arg329Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/setd2-p-arg472his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown